1. Field of the Invention
The present invention relates to complexes of .gamma.-cyclodextrin and retinol or retinol derivatives, to processes for their preparation and to their use.
2. The Prior Art
Cyclodextrins are cyclic oligosaccharides which are composed of 6, 7 or 8.alpha.(1-4)-linked anhydroglucose units. The .alpha.-, .beta.- or .gamma.-cyclodextrins prepared by the enzymatic conversion of starch differ in the diameter of their hydrophobic cavity and are generally suitable for inclusion of numerous lipophilic substances.
Retinol (vitamin A) is a fat-soluble vitamin composed of a cyclohexene ring with a side chain containing conjugated polyunsaturation. It is essential for humans inter alia and plays an important role particularly for vision. The daily requirement is met almost exclusively by the intake of .beta.-carotene (provitamin A), which is converted into retinol enzymatically.
Because of its important physiological function, especially for vision, and also its skincare and antiwrinkle properties, retinol is an extremely valuable substance. In the cosmetics industry, there is great interest in the increased use of vitamin A, particularly in dermatological formulations.
Topical application of retinol stabilizes the vitamin A balance in the skin, which balance can be permanently impaired in particular by exposure to UV light. The deficiency of vitamin A leads to damage, particularly of the epidermis, and to increased formation of wrinkles and horn ("photoaging"). There is also a loss of the skin's elasticity. Moreover, the skin's barrier function against microorganisms is weakened.
The main problem that prevents the wide spread use of retinol is its sensitivity to oxidation, in particular oxidation caused by exposure to light. An autoxidation reaction takes place at the side chain of the molecule which contains the conjugated unsaturation. This reaction leads to the formation of numerous decomposition products, to isomerizations and to polymerizations. The originally crystalline retinol material becomes a viscous mass; and the pale yellow color of pure retinol becomes noticeably darker. As a result of peroxides which are formed as intermediates, the potentially toxic results of using these formulations increases. Also, the cosmetically desired results of the remaining intact retinol are reduced.
Instead of using the uncombined free retinol, which is very sensitive to oxidation, cosmetics, especially antiwrinkle creams, therefore often contain the less effective, but more stable retinyl ester. Examples of these more stable retinyl esters particularly include retinyl acetate and retinyl palmitate.
Moreover, retinol containing vitamin preparations are being marketed by the food industry. Furthermore, retinol can be used in pharmaceutical formulations.
Procedures which have the beneficial result of stabilizing pure retinol are thus of exceptional interest. Because free or uncombined retinol is extremely sensitive to oxidative decomposition, its use is severely limited, even though free retinol is highly desirable per se.
U.S. Pat. No. 2,827,452 discloses how retinol and also retinyl acetate and retinyl palmitate can be stabilized using .beta.-cyclodextrin.
CA: 98:52237 describes the use of an .alpha.-cyclodextrin/retinol complex as an additive in food technology.
CA: 110:199059 describes how the photostability of retinyl acetate is increased by .beta.-cyclodextrin and .beta.-cyclodextrin derivatives in aqueous solution and in the solid state.
CA: 120:265222 discloses the complexation of retinyl acetate using .beta.-cyclodextrin.
WO 94/21225 describes a skincare formulation comprising retinyl palmitate and .beta.-cyclodextrin.
In WO 90/14082, retinoic acid is used together with .beta.-cyclodextrin in an aqueous gel for dermatological purposes.
U.S. Pat. No. 5,484,816 discloses the stabilization of vitamin A and its corresponding fatty acid esters, which may also be present in dermatological formulations, by using antioxidants and UV-absorbers in the form of cyclodextrin complexes.
J. Drug Targeting 2(5) (1994) 449-54 (CA: 122:64224) reports on the complexation of retinol and retinoic acid using hydroxypropyl-.beta.-cyclodextrin and on the inclusion of the corresponding complexes in liposomes.
U.S. Pat. No. 5,024,998 describes how, after parenteral application, the risk of undesired accumulation of retinol as a lipophilic pharmaceutical active substance can be lowered by solubilization using hydroxypropyl-.beta.-cyclodextrin.